Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen and they acquired their name because of their propensity to kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. Surprisingly little is known about receptors that activate the cytotoxic response of NK cells. A major goal of this project is to define the molecular basis of NK cell activation and to characterize the receptors involved. In addition, an in vivo model in mice has been developed to determine how activation and inhibition of NK cells and mast cells are controlled during exposure to various pathogens.The gp49B receptor has an inhibitory activity in both NK cells and mast cells. Mice deficient in the gp49B gene have been generated. Such gp49-deficient mice have been crossed for several generations with a congenic strain of mice in order to obtain a fairly pure genetic background. NK cells developed normally in gp49B-deficient mice and displayed normal cytotoxic activity in vitro. Likewise, mast cells developed normally in gp49B-deficient mice and displayed normal degranulation activity in vitro. The healthy status of gp49B-null mice makes them very suitable for testing the role of gp49B in controlling immune responses during infections, in particular those known to elicit NK or mast cell responses.